This invention relates generally to modulators of chemokine receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatory diseases, allergic and autoimmune diseases, and in particular, asthma, rheumatoid arthritis, atherosclerosis, and multiple sclerosis.
Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in: Luster, New Eng. J. Med. 1998, 338, 436-445 and Rollins, Blood 1997, 90, 909-928). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1xcex1, MIP-1xcex2, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (xe2x88x921 and xe2x88x922) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.
The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in: Horuk, Trends Pharm. Sci. 1994, 15, 159-165) which are termed xe2x80x9cchemokine receptors.xe2x80x9d On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns: CCR-1 (or xe2x80x9cCKR-1xe2x80x9d or xe2x80x9cCC-CKR-1xe2x80x9d) [MIP-1xcex1, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell 1993, 72, 415-425, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-2A and CCR-2B (or xe2x80x9cCKR-2Axe2x80x9d/xe2x80x9cCKR-2Bxe2x80x9d or xe2x80x9cCC-CKR-2Axe2x80x9d/xe2x80x9cCC-CKR-2Bxe2x80x9d) [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo, et al., Proc. Natl. Acad. Sci. USA 1994, 91, 2752-2756, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-3 (or xe2x80x9cCKR-3xe2x80x9d or xe2x80x9cCC-CKR-3xe2x80x9d) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem. 1995, 270, 16491-16494, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-4 (or xe2x80x9cCKR-4xe2x80x9d or xe2x80x9cCC-CKR-4xe2x80x9d) [TARC, MIP-1xcex1, RANTES, MCP-1] (Power, et al., J. Biol. Chem. 1995, 270, 19495-19500, and Luster, New Eng. J. Med. 1998, 338, 436-445); CCR-5 (or xe2x80x9cCKR-5xe2x80x9d OR xe2x80x9cCC-CKR-5xe2x80x9d) [MIP-1xcex1, RANTES, MIP-1xcex2] (Sanson, et al., Biochemistry 1996, 35, 3362-3367); CCR-6 (or xe2x80x9cCKR-6xe2x80x9d or xe2x80x9cCC-CKR-6xe2x80x9d) [LARC] (Baba, et al., J. Biol. Chem. 1997, 272, 14893-14898); CCR-7 (or xe2x80x9cCKR-7xe2x80x9d or xe2x80x9cCC-CKR-7xe2x80x9d) [ELC] (Yoshie et al., J. Leukoc. Biol. 1997, 62, 634-644); CCR-8 (or xe2x80x9cCKR-8xe2x80x9d or xe2x80x9cCC-CKR-8xe2x80x9d) [I-309, TARC, MIP-1xcex2] (Napolitano et al., J. Immunol., 1996, 157, 2759-2763, and Bernardini, et al., Eur. J. Immunol. 1998, 28, 582-588); CCR-10 (or xe2x80x9cCKR-10xe2x80x9d or xe2x80x9cCC-CKR-10xe2x80x9d) [MCP-1, MCP-3] (Bonini, et al., DNA and Cell Biol. 1997, 16, 1249-1256); and CCR-11 [MCP-1, MCP-2, and MCP-4] (Schweickert, et al., J. Biol. Chem. 2000, 275, 90550).
In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed in: Wells and Schwartz, Curr. Opin. Biotech. 1997, 8, 741-748). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
The chemokines and their cognate receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis (reviewed in: Bharat K. Trivedi, et al, Ann. Reports Med. Chem. 2000, 35, 191; John Saunders and Christine M. Tarby, Drug Disc. Today 1999, 4, 80; Brett A. Premack and Thomas J. Schall, Nature Medicine 1996, 2, 1174). For example, the chemokine monocyte chemoattractant-1 (MCP-1) and its receptor CC Chemokine Receptor 2 (CCR-2) play a pivotal role in attracting leukocytes to sites of inflammation and in subsequently activating these cells. When the chemokine MCP-1 binds to CCR-2, it induces a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of leukocyte migration. Demonstration of the importance of the MCP-1/CCR-2 interaction has been provided by experiments with genetically modified mice. MCP-1 xe2x88x92/xe2x88x92 mice had normal numbers of leukocytes and macrophages, but were unable to recruit monocytes into sites of inflammation after several different types of immune challenge (Bao Lu, et al., J. Exp. Med. 1998, 187, 601). Likewise, CCR-2 xe2x88x92/xe2x88x92 mice were unable to recruit monocytes or produce interferon-xcex3 when challenged with various exogenous agents; moreover, the leukocytes of CCR-2 null mice did not migrate in response to MCP-1 (Landin Boring, et al., J. Clin. Invest. 1997, 100, 2552), thereby demonstrating the specificity of the MCP-1/CCR-2 interaction. Two other groups have independently reported equivalent results with different strains of CCR-2 xe2x88x92/xe2x88x92 mice (William A. Kuziel, et al., Proc. Natl. Acad. Sci. USA 1997, 94, 12053, and Takao Kurihara, et al., J. Exp. Med. 1997, 186, 1757). The viability and generally normal health of the MCP-1 xe2x88x92/xe2x88x92 and CCR-2 xe2x88x92/xe2x88x92 animals is noteworthy, in that disruption of the MCP-1/CCR-2 interaction does not induce physiological crisis. Taken together, these data lead one to the conclusion that molecules that block the actions of MCP-1 would be useful in treating a number of inflammatory and autoimmune disorders. This hypothesis has now been validated in a number of different animal disease models, as described below.
Several studies have demonstrated the potential therapeutic value of antagonism of the MCP-1/CCR2 interaction in treating rheumatoid arthritis. A DNA vaccine encoding MCP-1 was shown recently to ameliorate chronic polyadjuvant-induced arthritis in rats (Sawsan Youssef, et al., J. Clin. Invest. 2000, 106, 361). Likewise, inflammatory disease symptoms could be controlled via direct administration of antibodies for MCP-1 to rats with collagen-induced arthritis (Hiroomi Ogata, et al., J. Pathol. 1997, 182, 106), or streptococcal cell wall-induced arthritis (Ralph C. Schimmer, et al., J. Immunol. 1998, 160, 1466). Perhaps most significantly, a peptide antagonist of MCP-1, MCP-1(9-76), was shown both to prevent disease onset and to reduce disease symptoms (depending on the time of administration) in the MRL-lpr mouse model of arthritis (Jiang-Hong Gong, et al., J. Exp. Med. 1997, 186, 131).
Three key studies have demonstrated the potential therapeutic value of antagonism of the MCP-1/CCR2 interaction in treating atherosclerosis. For example, when MCP-1 xe2x88x92/xe2x88x92 mice are mated with LDL receptor-deficient mice, an 83% reduction in aortic lipid deposition was observed (Long Gu, et al., Mol. Cell 1998, 2, 275). Similarly, when MCP-1 was genetically ablated from mice which already overexpressed human apolipoprotein B, the resulting mice were protected from atherosclerotic lesion formation relative to the MCP-1 +/+ apoB control mice (Jennifa Gosling, et al., J. Clin. Invest. 1999, 103, 773). Likewise, when CCR-2 xe2x88x92/xe2x88x92 mice are crossed with apolipoprotein E mice, a significant decrease in the incidence of atherosclerotic lesions was observed (Landin Boring, et al, Nature 1998, 394, 894).
Other studies have demonstrated the potential therapeutic value of antagonism of the MCP-1/CCR-2 interaction in treating multiple sclerosis; all of these studies have been demonstrated in experimental autoimmune encephalomyelitis (EAE), the standard animal model for multiple scelerosis. Administration of antibodies for MCP-1 to animals with EAE significantly diminished disease relapse (K. J. Kennedy, et al., J. Neuroimmunol. 1998, 92, 98). Furthermore, two recent reports have now shown that CCR-2 xe2x88x92/xe2x88x92 mice are resistant to EAE (Brian T. Fife, et al., J. Exp. Med. 2000, 192, 899; Leonid Izikson, et al., J. Exp. Med. 2000, 192, 1075).
Other studies have demonstrated the potential therapeutic value of antagonism of the MCP-1/CCR2 interaction in treating asthma. Sequestration of MCP-1 with a neutralizing antibody in ovalbumin-challenged mice resulted in marked decrease in bronchial hyperresponsiveness and inflammation (Jose-Angel Gonzalo, et al., J. Exp. Med. 1998, 188, 157). It proved possible to reduce allergic airway inflammation in Schistosoma mansoni egg-challenged mice through the administration of antibodies for MCP-1 (Nicholas W. Lukacs, et al., J. Immunol. 1997, 158, 4398). Consistent with this, MCP-1 xe2x88x92/xe2x88x92 mice displayed a reduced response to challenge with Schistosoma mansoni egg (Bao Lu, et al., J. Exp. Med. 1998, 187, 601).
Other studies have demonstrated the potential therapeutic value of antagonism of the MCP-1/CCR2 interaction in treating kidney disease. Administration of antibodies for MCP-1 in a murine model of glomerularnephritis resulted in a marked decrease in glomerular crescent formation and deposition of type I collagen (Clare M. Lloyd, et al., J. Exp. Med. 1997, 185, 1371). In addition, MCP-1 xe2x88x92/xe2x88x92 mice with induced nephrotoxic serum nephritis showed significantly less tubular damage than their MCP-1 +/+ counterparts (Gregory H. Tesch, et al., J. Clin. Invest. 1999, 103, 73).
One study has demonstrated the potential therapeutic value of antagonism of the MCP-1/CCR2 interaction in treating systemic lupus erythematosus. Crossing of MCP-1 xe2x88x92/xe2x88x92 mice with MRL-FASlpr micexe2x80x94the latter of which have a fatal autoimmune disease that is analogous to human systemic lupus erythematosusxe2x80x94results mice that have less disease and longer survival than the wildtype MRL-FASlpr mice (Gregory H. Tesch, et al., J. Exp. Med. 1999, 190, 1813).
One study has demonstrated the potential therapeutic value of antagonism of the MCP-1/CCR2 interaction in treating colitis. CCR-2 xe2x88x92/xe2x88x92 mice were protected from the effects of dextran sodium sulfate-induced colitis (Pietro G. Andres, et al., J. Immunol. 2000, 164, 6303).
One study has demonstrated the potential therapeutic value of antagonism of the MCP-1/CCR2 interaction in treating alveolitis. When rats with IgA immune complex lung injury were treated intravenously with antibodies raised against rat MCP-1 (JE), the symptoms of alveolitis were partially aleviated (Michael L. Jones, et al., J. Immunol. 1992, 149, 2147).
Other studies have provided evidence that MCP-1 is overexpressed in various disease states not mentioned above. These reports provide strong correlative evidence that MCP-1 antagonists could be useful therapeutics for such diseases. Two reports described the overexpression of MCP-1 in the intestinal epithelial cells and bowel mucosa of patients with inflammatory bowel disease (H. C. Reinecker, et al., Gastroenterology 1995, 108, 40, and Michael C. Grimm, et al., J. Leukoc. Biol. 1996, 59, 804). Two reports describe the overexpression of MCP-1 rats with induced brain trauma (J. S. King, et al., J. Neuroimmunol. 1994, 56, 127, and Joan W. Berman, et al., J. Immunol. 1996, 156, 3017). Another study has demonstrated the overexpression of MCP-1 in rodent cardiac allografts, suggesting a role for MCP-1 in the pathogenesis of transplant arteriosclerosis (Mary E. Russell, et al. Proc. Natl. Acad. Sci. USA 1993, 90, 6086). The overexpression of MCP-1 has been noted in the lung endothelial cells of patients with idiopathic pulmonary fibrosis (Harry N. Antoniades, et al., Proc. Natl. Acad. Sci. USA 1992, 89, 5371). Similarly, the overexpression of MCP-1 has been noted in the skin from patients with psoriasis (M. Deleuran, et al., J. Dermatol. Sci. 1996, 13, 228, and R. Gillitzer, et al., J. Invest. Dermatol. 1993, 101, 127). Finally, a recent report has shown that MCP-1 is overexpressed in the brains and cerebrospinal fluid of patients with HIV-1-associated dementia (Alfredo Garzino-Demo, WO 99/46991).
It should also be noted that CCR-2 has been implicated as a co-receptor for some strains of HIV (B. J. Doranz, et al., Cell 1996, 85, 1149). It has also been determined that the use of CCR-2 as an HIV co-receptor can be correlated with disease progression (Ruth I. Connor, et al., J. Exp. Med. 1997, 185, 621). This finding is consistent with the recent finding that the presence of a CCR-2 mutant, CCR2-64I, is positively correlated with delayed onset of HIV in the human population (Michael W. Smith, et al., Science 1997, 277, 959). Although MCP-1 has not been implicated in these processes, it may be that MCP-1 antagonists that act via binding to CCR-2 may have beneficial therapeutic effects in delaying the disease progression to AIDS in HIV-infected patients.
Recently, a number of groups have described the development of small molecule antagonists of MCP-1 (reviewed in: Bharat K. Trivedi, et al, Ann. Reports Med. Chem. 2000, 35, 191). Workers at Teijen and Combichem reported the use of cyclic amines (A) as MCP-1 (Tatsuki Shiota, et al., WO 99/25686; Tatsuki Shiota, et al., WO 00/69815) and MIP-1xcex1 (Christine Tarby and Wilna Moree, WO 00/69820) antagonists. These compounds are distinguished from those of the present invention (I) by the requirement for the central cyclic amine grouping. 
A number of other groups have also described the a development of small molecule antagonists of the MCP-1/CCR-2 interaction. To date, indolopiperidines (Ian T. Forbes, et al. , Bioorg. Med. Chem. Lett. 2000, 10, 1803), spiropiperidines (Tara Nirzadegan, et al., J. Biol. Chem. 2000, 275, 25562), quaternary amines (Masanori Baba, et al., Proc. Natl. Acad. Sci. 1999, 96, 5698), 2-substituted indoles (Alan Faull and Jason Kettle, WO 00/46196; Andrew John Barker, et al., WO 99/07351; Andrew John Barker, et al., WO 99/07678), pyrazolone derivatives (Janak Khimchand Padia, et al., U.S. Pat. No. 6,011,052, 2000), 2-substituted benzimidazoles (David Thomas Connor, et al., WO 98/06703), N,N-dialkylhomopiperazines (T. Shiota, et al., WO 97/44329), bicyclic pyrroles (Andrew J. Barker, et al., WO 99/40913 and Andrew J. Barker, et al., WO 99/40914), and 5-aryl pentadienamides (K. G. Carson, et al., Cambridge Health Tech Institute Chemokine Symposium, McLean, Va., USA, 1999) have all been reported as MCP-1 antagonists. The foregoing reference compounds are readily distinguished structurally from the present invention by virtue of substantial differences in the terminal functionality, the attachment functionality, or the core functionality. The prior art does not disclose nor suggest the unique combination of structural fragments that embody in the novel compounds described herein. Furthermore, the prior art does not disclose or suggest that the compounds of the present invention would be antagonists of MCP-1.
It should be noted that CCR-2 is also the receptor for the chemokines MCP-2, MCP-3, MCP-4, and MCP-5 (Luster, New Eng. J. Med. 1998, 338, 436-445). Since it is presumed that the new compounds of formula (I) described herein antagonize MCP-1 by binding to the CCR-2 receptor, it may be that these compounds of formula (I) are also effective antagonists of the actions of MCP-2, MCP-3, MCP-4, and MCP-5 that are mediated by CCR-2. Accordingly, when reference is made herein to xe2x80x9cantagonism of MCP-1,xe2x80x9d it is to be assumed that this is equivalent to xe2x80x9cantagonism of chemokine stimulation of CCR-2.xe2x80x9d
Accordingly, the present invention provides novel antagonists or partial agonists/antagonists of MCP-1 receptor activity, or pharmaceutically acceptable salts or prodrugs thereof.
The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a method for treating rheumatoid arthritis, multiple sclerosis, and atherosclerosis, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a method for treating inflammatory diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides novel cyclic derivatives for use in therapy.
The present invention provides the use of novel cyclic derivatives for the manufacture of a medicament for the treatment of inflammatory diseases.
These and other features of the invention, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein Z, m, n, s, R1, R1a, R1b, R2, R8, R9, R10, R10a, R11, R12, and R13 are defined below, are effective modulators of chemokine activity.
[1] Thus, in a First Embodiment, the Present Invention Provides Novel Compounds of Formula (I) 
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein the cycloalkyl group is saturated or partially unsaturated; or a heterocycle of 3 to 7 atoms wherein the heterocycle is saturated or partially unsaturated, the heterocycle containing a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, and xe2x80x94N(R4)xe2x80x94, the heterocycle optionally containing a xe2x80x94C(O)xe2x80x94; ring B being substituted with 0-2 R5;
Z is selected from a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(S)NHxe2x80x94, xe2x80x94SO2xe2x80x94, and xe2x80x94SO2NHxe2x80x94;
R1a and R1b are independently selected from H, C1-4 alkyl, C1-4 cycloalkyl, CF3, or alternatively, R1a and R1b are taken together to from xe2x95x90O;
R1 is selected from a C6-10 aryl group substituted with 0-5 R6 and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R6;
R2 is selected from a C6-10 aryl group substituted with 0-5 R7 and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7;
R4 is selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, (CRR)qOH, (CRR)tSH, (CRR)tOR4d, (CHR)tSR4d, (CRR)tNR4aR4a, (CRR)qC(O)OH, (CRR)rC(O)R4b, (CRR)rC(O)NR4aR4a, (CRR)tOC(O)NR4aR4a, (CRR)tNR4aC(O)OR4d, (CRR)tNR4aC(O)R4b, (CRR)rC(O)OR4b, (CRR)tOC(O)R4b, (CRR)rS(O)pR4b, (CRR)rS(O)2NR4aR4a, (CRR)rNR4aS(O)2R4b, C1-6 haloalkyl, a (CRR)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R4e, and a (CHR)r-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R4e;
R4a, at each occurrence, is independently selected from H, methyl substituted with 0-1 R4c, C2-6 alkyl substituted with 0-3 R4e, C3-8 alkenyl substituted with 0-3 R4e, C3-8 alkynyl substituted with 0-3 R4e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-4 R4e, and a (CHR)r-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R4e;
R4b, at each occurrence, is selected from H, C1-6 alkyl substituted with 0-3 R4e, C3-8 alkenyl substituted with 0-3 R4e, C3-8 alkynyl substituted with 0-3 R4e, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R4e, and a (CHR)r-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R4e;
R4c is independently selected from xe2x80x94C(O)R4b, xe2x80x94C(O)OR4d, xe2x80x94C(O)NR4fR4f, and (CH2)rphenyl;
R4d, at each occurrence, is selected from methyl, CF3, C1-6 alkyl substituted with 0-3 R4e, C3-8 alkenyl substituted with 0-3 R4e, C3-8 alkynyl substituted with 0-3 R4e, and a C3-10 carbocyclic residue substituted with 0-3 R4e;
R4e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR4fR4f, xe2x80x94C(O)R4i, xe2x80x94C(O)OR4j, xe2x80x94C(O)NR4hR4h, xe2x80x94OC(O)NR4hR4h, xe2x80x94NR4hC(O)NR4hR4h, xe2x80x94NR4hC(O)OR4j, and (CH2)rphenyl;
R4f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R4h, at each occurrence, is independently selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, and a (CH2)rxe2x80x94C3-10 carbocyclic;
R4i, at each occurrence, is selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, and a (CH2)rxe2x80x94C3-6 carbocyclic residue;
R4j, at each occurrence, is selected from CF3, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, and a C3-10 carbocyclic residue;
R5, at each occurrence, is independently selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CRR)rOH, (CRR)rSH, (CRR)rOR5d, (CRR)rSR5d, (CRR)rNR5aR5a, (CRR)rC(O)OH, (CRR)rC(O)R5b, (CRR)rC(O)NR5aR5a, (CRR)rNR5aC(O)R5b, (CRR)rOC(O)NR5aR5a, (CRR)rNR5aC(O)OR5d, (CRR)rNR5aC(O)NR5aR5a, (CRR)rNR5aC(O)H, (CRR)rC(O)OR5b, (CRR)rOC(O)R5b, (CRR)rS(O)pR5b, (CRR)rS(O)2NR5aR5a, (CRR)rNR5aS(O)2R5b, (CRR)rNR5aS(O)2NR5aR5a, C1-6 haloalkyl, a (CRR)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R5c, and a (CRR)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R5c;
R5a, at each occurrence, is independently selected from H, methyl substituted with 0-1 R5g, C2-6 alkyl substituted with 0-2 R5e, C3-8 alkenyl substituted with 0-2 R5e, C3-8 alkynyl substituted with 0-2 R5e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R5e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R5e;
R5b, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 R5e, C3-8 alkenyl substituted with 0-2 R5e, C3-8 alkynyl substituted with 0-2 R5e, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R5e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R5e;
R5c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR5fR5f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R5b, (CH2)rC(O)NR5fR5f, (CH2)rNR5fC(O)R5b, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R5b, (CH2)rC(xe2x95x90NR5f)NR5fR5f, (CH2)rS(O)pR5b, (CH2)rNHC(xe2x95x90NR5f)NR5fR5f, (CH2)rS(O)2NR5fR5f, (CH2)rNR5fS(O)2R5b, and (CH2)rphenyl substituted with 0-3 R5e;
R5d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-2 R5e, C3-8 alkenyl substituted with 0-2 R5e, C3-8 alkynyl substituted with 0-2 R5e, and a C3-10 carbocyclic residue substituted with 0-3 R5e;
R5e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3,(CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR5fR5f, and (CH2)rphenyl;
R5f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R5g is independently selected from xe2x80x94C(O)R5b, xe2x80x94C(O)OR5d, xe2x80x94C(O)NR5fR5f, and (CH2)rphenyl;
R, at each occurrence, is selected from H, C1-6 alkyl substituted with R5e, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R5e;
R6, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CRxe2x80x2Rxe2x80x2)rNR6aR6a, (CRxe2x80x2Rxe2x80x2)rOH, (CRxe2x80x2Rxe2x80x2)rO(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rSH, (CRxe2x80x2Rxe2x80x2)rC(O)H, (CRxe2x80x2Rxe2x80x2)rS(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rSC(O)(CRxe2x80x2Rxe2x80x2)rR6b, (CRxe2x80x2Rxe2x80x2)rC(O)OH, (CRxe2x80x2Rxe2x80x2)rC(O)(CRxe2x80x2Rxe2x80x2)rR6b, (CRxe2x80x2Rxe2x80x2)rNR6aR6a, (CRxe2x80x2Rxe2x80x2)rC(O)NR6aR6a, (CRxe2x80x2Rxe2x80x2)rNR6fC(O)(CRxe2x80x2Rxe2x80x2)rR6b, (CRxe2x80x2Rxe2x80x2)rC(O)O(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rOC(O)(CRxe2x80x2Rxe2x80x2)rR6b, (CRxe2x80x2Rxe2x80x2)rOC(O)NR6a(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rNR6aC(O)NR6a(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rNR6aC(S)NR6a(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rNR6fC(O)O(CRxe2x80x2Rxe2x80x2)rR6b, (CRxe2x80x2Rxe2x80x2)rC(xe2x95x90NR6f)NR6aR6a, (CRxe2x80x2Rxe2x80x2)rNHC(xe2x95x90NR6f)NR6fR6f, (CRxe2x80x2Rxe2x80x2)rS(O)p(CRxe2x80x2Rxe2x80x2)rR6b, (CRxe2x80x2Rxe2x80x2)rS(O)2NR6aR6a, (CRxe2x80x2Rxe2x80x2)rNR6fS(O)2NR6aR6a, (CRxe2x80x2Rxe2x80x2)rNR6fS(O)2(CRxe2x80x2Rxe2x80x2)rR6b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, and (CRxe2x80x2Rxe2x80x2)rphenyl substituted with 0-3 R6e;
alternatively, two R6 on adjacent atoms on R1 may join to form a cyclic acetal;
R6a, at each occurrence, is selected from H, methyl substituted with 0-1 R6g, C2-6 alkyl substituted with 0-2 R6e, C3-8 alkenyl substituted with 0-2 R6e, C3-8 alkynyl substituted with 0-2 R6e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R6e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R6e;
R6b, at each occurrence, is selected from H, C1-6 alkyl substituted with 0-2 R6e, C3-8 alkenyl substituted with 0-2 R6e, C3-8 alkynyl substituted with 0-2 R6e, a (CH2)rC3-6 carbocyclic residue substituted with 0-3 R6e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R6e;
R6d, at each occurrence, is selected from C3-8 alkenyl substituted with 0-2 R6e, C3-8 alkynyl substituted with 0-2 R6e, methyl, CF3, C2-6 alkyl substituted with 0-3 R6e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R6e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R6e;
R6e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR6fR6f, and (CH2)rphenyl;
R6f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
R6g is independently selected from xe2x80x94C(O)R6b, xe2x80x94C(O)OR6d, xe2x80x94C(O)NR6fR6f, and (CH2)rphenyl;
R7, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CRxe2x80x2Rxe2x80x2)rNR7aR7a, (CRxe2x80x2Rxe2x80x2)rOH, (CRxe2x80x2Rxe2x80x2)rO(CRxe2x80x2Rxe2x80x2)rR7d, (CRxe2x80x2Rxe2x80x2)rSH, (CRxe2x80x2Rxe2x80x2)rC(O)H, (CRxe2x80x2Rxe2x80x2)r(CRxe2x80x2Rxe2x80x2)rR7d, (CRxe2x80x2Rxe2x80x2)rC(O)OH, (CRxe2x80x2Rxe2x80x2)rC(O)(CRxe2x80x2Rxe2x80x2)rR7b, (CRxe2x80x2Rxe2x80x2)rC(O)NR7aR7a, (CRxe2x80x2Rxe2x80x2)rNR7fC(O)(CRxe2x80x2Rxe2x80x2)rR7b, (CRxe2x80x2Rxe2x80x2)rC(O)O(CRxe2x80x2Rxe2x80x2)rR7d, (CRxe2x80x2Rxe2x80x2)rOC(O)(CRxe2x80x2Rxe2x80x2)rR7b, (CRxe2x80x2Rxe2x80x2)rOC(O)NR7a(CRxe2x80x2Rxe2x80x2)rR7a, (CRxe2x80x2Rxe2x80x2)rNR7aC(O)NR7a(CRxe2x80x2Rxe2x80x2)rR7a, (CRxe2x80x2Rxe2x80x2)rNR7fC(O)O(CRxe2x80x2Rxe2x80x2)rR7b, (CRxe2x80x2Rxe2x80x2)rC(xe2x95x90NR7f)NR7aR7a, (CRxe2x80x2Rxe2x80x2)rNHC(xe2x95x90NR7f)NR7fR7f, (CRxe2x80x2Rxe2x80x2)rS(O)p(CRxe2x80x2Rxe2x80x2)rR7b, (CRxe2x80x2Rxe2x80x2)rS(O)2NR7aR7a, (CRxe2x80x2Rxe2x80x2)rNR7aS(O)2NR7aR7a, (CRxe2x80x2Rxe2x80x2)rNR7fS(O)2(CRxe2x80x2Rxe2x80x2)rR7b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, and (CRxe2x80x2Rxe2x80x2)rphenyl substituted with 0-3 R7e;
alternatively, two R7 on adjacent atoms on R2 may join to form a cyclic acetal;
R7a, at each occurrence, is independently selected from H, methyl substituted with 0-1 R7g, C2-6 alkyl substituted with 0-2 R7e, C3-8 alkenyl substituted with 0-2 R7e, C3-8 alkynyl substituted with 0-2 R7e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R7e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl substituted with 0-2 R7e, C3-8 alkenyl substituted with 0-2 R7e, C3-8 alkynyl substituted with 0-2 R7e, a (CH2)rC3-6 carbocyclic residue substituted with 0-3 R7e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7e;
R7d, at each occurrence, is selected from C3-8 alkenyl substituted with 0-2 R7e, C3-8 alkynyl substituted with 0-2 R7e, methyl, CF3, C2-6 alkyl substituted with 0-3 R7e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R7e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
R7f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
R7g is independently selected from xe2x80x94C(O)R7b, xe2x80x94C(O)OR7d, xe2x80x94C(O)NR7fR7f, and (CH2)rphenyl;
Rxe2x80x2, at each occurrence, is selected from H, C1-6 alkyl substituted with R6e, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R6e;
R8 is selected from H, C1-4 alkyl, and C3-4 cycloalkyl;
R9 is selected from H, C1-4 alkyl, C3-4 cycloalkyl, and (CH2)xe2x80x94R1;
R10 and R10a are independently selected from H, and C1-4alkyl substituted with 0-1 R10b,
alternatively, R10 and R10a can join to form a C3-6 cycloalkyl;
R10b, at each occurrence, is independently selected from xe2x80x94OH, xe2x80x94SH, xe2x80x94NR10cR10c, xe2x80x94C(O)NR10cR10c, and xe2x80x94NHC(O)R10c;
R10c is selected from H, C1-4 alkyl and C3-6 cycloalkyl;
R11 is selected from H, C1-4 alkyl, (CHR)qOH, (CHR)qSH, (CHR)qOR11d, (CHR)qS(O)pR11d, (CHR)rC(O)R11b, (CHR)rNR11aR11a, (CHR)rC(O)NR11aR11a, (CHR)rC(O)NR11aOR11d, (CHR)qNR11aC(O)R11b, (CHR)qNR11aC(O)OR11d, (CHR)qOC(O)NR11aR11a, (CHR)rC(O)OR11d, a (CHR)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R11e, and a (CHR)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11a, at each occurrence, is independently selected from H, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, (CH2)rC3-6 cycloalkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11b, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11d, at each occurrence, is independently selected from H, methyl, xe2x80x94CF3, C2-4 alkyl, C3-6 alkenyl, C3-6 alkynyl, a C3-6 carbocyclic residue substituted with 0-3 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, xe2x80x94Oxe2x80x94C1-6 alkyl, SH, (CH2)rSC1-5 alkyl, (CH2)rNR11fR11f, and (CH2)rphenyl;
R11f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R12 is selected from H, C1-4 alkyl, (CHR)qOH, (CHR)qSH, (CHR)qOR12d, (CHR)qS(O)pR12d, (CHR)rC(O)R12b, (CHR)rNR12aR12a, (CHR)rC(O)NR12aR12a, (CHR)rC(O)NR12aOR12d, (CHR)qNR12aC(O)R12b, (CHR)qNR12aC(O)COR12d, (CHR)qOC(O)NR12aR12a, (CHR)rC(O)OR12d, a (CHR)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R12e, and a (CHR)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12a, at each occurrence, is independently selected from H, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, (CH2)rC3-6 cycloalkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R12e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12b, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R12e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12d, at each occurrence, is independently selected from H, methyl, xe2x80x94CF3, C2-4 alkyl, C3-6 alkenyl, C3-6 alkynyl, a C3-6 carbocyclic residue substituted with 0-3 R12e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, xe2x80x94Oxe2x80x94C1-6 alkyl, SH, (CH2)rSC1-5 alkyl, (CH2)rNR12fR12f, and (CH2)rphenyl;
R12f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R13, at each occurrence, is independently selected from methyl, C2-4 alkyl substituted with 0-1 R13b;
R13b is selected from xe2x80x94OH, xe2x80x94SH, xe2x80x94NR13cR13c, xe2x80x94C(O)NR13cR13c, and xe2x80x94NHC(O)R13c;
R13c is selected from H, C1-4 alkyl and C3-6 cycloalkyl;
n is selected from 1 and 2;
m is selected from 0 and 1;
p, at each occurrence, is independently selected from 0, 1, and 2;
q, at each occurrence, is independently selected from 1, 2, 3, and 4;
r, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
s, at each occurrence, is independently selected from 0 and 1; and
t, at each occurrence, is independently selected from 2, 3, and 4.
[2] Thus, in a Another Embodiment, the Present Invention Provides Novel Compounds of Formula (I) 
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
ring B is a cycloalkyl group of 3 to 8 carbon atoms wherein the cycloalkyl group is saturated or partially unsaturated; or a heterocycle of 3 to 7 atoms wherein the heterocycle is saturated or partially unsaturated, the heterocycle containing a heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, and xe2x80x94N(R4)xe2x80x94, the heterocycle optionally containing a xe2x80x94C(O)xe2x80x94; ring B being substituted with 0-2 R5;
Z is selected from a bond, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(S)NHxe2x80x94, xe2x80x94SO2xe2x80x94, and xe2x80x94SO2NHxe2x80x94;
R1a and R1b are independently selected from H, C1-4 alkyl, C1-4 cycloalkyl, CF3, or alternatively, R1a and R1b are taken together to from xe2x95x90O;
R1 is selected from a C6-10 aryl group substituted with 0-5 R6 and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R6;
R2 is selected from a C6-10 aryl group substituted with 0-5 R7 and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7;
R4 is selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, (CRR)qOH, (CRR)tSH, (CRR)tOR4d, (CHR)tSR4d, (CRR)tNR4aR4a, (CRR)qC(O)OH, (CRR)rC(O)R4b, (CRR)rC(O)NR4aR4a, (CRR)tOC(O)NR4aR4a, (CRR)tNR4aC(C)OR4d, (CRR)tNR4aC(O)R4b, (CRR)rC(O)OR4b, (CRR)tOC(O)R4b, (CRR)rS(O)pR4b, (CRR)rS(O)2NR4aR4a, (CRR)rNR4aS(O)2R4b, C1-6 haloalkyl, a (CRR)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R4e, and a (CHR)r-4-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R4e;
R4a, at each occurrence, is independently selected from H, methyl substituted with 0-1 R4c, C2-6 alkyl substituted with 0-3 R4e, C3-8 alkenyl substituted with 0-3 R4e, C3-8 alkynyl substituted with 0-3 R4e, and a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-4 R4e;
R4b, at each occurrence, is selected from H, C1-6 alkyl substituted with 0-3 R4e, C3-8 alkenyl substituted with 0-3 R4e, C3-8 alkynyl substituted with 0-3 R4e, and a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R4e;
R4c is independently selected from xe2x80x94C(O)R4b, xe2x80x94C(O)OR4d, xe2x80x94C(O)NR4fR4f, and (CH2)rphenyl;
R4d, at each occurrence, is selected from methyl, CF3, C1-6 alkyl substituted with 0-3 R4e, C3-8 alkenyl substituted with 0-3 R4e, C3-8 alkynyl substituted with 0-3 R4e, and a C3-10 carbocyclic residue substituted with 0-3 R4e;
R4e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR4fR4f, xe2x80x94C(O)R4i, xe2x80x94C(O)OR4i, xe2x80x94C(O)NR4hR4h, xe2x80x94OC(O)NR4hR4h, xe2x80x94NR4hC(O)NR4hR4h, xe2x80x94NR4hC(O) OR4j, and (CH2)rphenyl;
R4f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R4h, at each occurrence, is independently selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, and a (CH2)rxe2x80x94C3-10 carbocyclic;
R4i, at each occurrence, is selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, and a (CH2)rxe2x80x94C3-6 carbocyclic residue;
R4j, at each occurrence, is selected from CF3, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, and a C3-10 carbocyclic residue;
R5, at each occurrence, is independently selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CRR)rOH, (CRR)rSH, (CRR)rOR5d, (CRR)rSR5d, (CRR)rNR5aR5a, (CRR)rC(O)OH, (CRR)rC(O)R5b, (CRR)rC(O)NR5aR5a, (CRR)rNR5aC(O)R5b, (CRR)rOC(O)NR5aR5a, (CRR)rNR5aC(O)OR5d, (CRR)rNR5aC(O)NR5aR5a, (CRR)rNR5aC(O)H, (CRR)rC(O)OR5b, (CRR)rOC(O)R5b, (CRR)rS(O)pR5b, (CRR)rS(O)2NR5aR5a, (CRR)rNR5aS(O)2R5b, (CRR)rNR5aS(O)2 NR5aR5a, C1-6 haloalkyl, a (CRR)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R5c, and a (CRR)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R5c;
R5a, at each occurrence, is independently selected from H, methyl substituted with 0-1 R5g, C2-6 alkyl substituted with 0-2 R5e, C3-8 alkenyl substituted with 0-2 R5e, C3-8 alkynyl substituted with 0-2 R5e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R5e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R5e;
R5b, at each occurrence, is selected from C1-6 alkyl substituted with 0-3 R5e, C3-8 alkenyl substituted with 0-2 R5e, C3-8 alkynyl substituted with 0-2 R5e, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R5e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R5e;
R5c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR5fR5f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R5b, (CH2)rC(O)NR5fR5f, (CH2)rNR5fC(O)R5b, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R5b, (CH2)rC(xe2x95x90NR5f)NR5fR5f, (CH2),S(O)pR5b, (CH2)rNHC(xe2x95x90NR5f)NR5fR5f, (CH2)rS(O)2NR5fR5f, (CH2)rNR5fS(O)2R5b, and (CH2)rphenyl substituted with 0-3 R5e;
R5d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-2 R5e, C3-8 alkenyl substituted with 0-2 R5e, C3-8 alkynyl substituted with 0-2 R5e, and a C3-10 carbocyclic residue substituted with 0-3 R5e;
R5e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR5fR5f, and (CH2)rphenyl; R5f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R5g is independently selected from xe2x80x94C(O)R5b, xe2x80x94C(O)OR5d, xe2x80x94C(O)NR5fR5f, and (CH2)rphenyl;
R, at each occurrence, is selected from H, C1-6 alkyl substituted with R5e, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R5e;
R6, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CRxe2x80x2Rxe2x80x2)rNR6aR6a, (CRxe2x80x2Rxe2x80x2)rOH, (CRxe2x80x2Rxe2x80x2)rO(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rSH, (CRxe2x80x2Rxe2x80x2)rC(O)H, (CRxe2x80x2Rxe2x80x2)rS(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rC(O)OH, (CRxe2x80x2Rxe2x80x2)rC(O)(CRxe2x80x2Rxe2x80x2)rR6b, (CRxe2x80x2Rxe2x80x2)rNR6aR6a, (CRxe2x80x2Rxe2x80x2)rC(O)NR6aR6a, (CRxe2x80x2Rxe2x80x2)rNR6fC(O)(CRxe2x80x2Rxe2x80x2)rR6b, (CRxe2x80x2Rxe2x80x2)rC(O)O(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rOC(O)(CRxe2x80x2Rxe2x80x2)rR6b, (CRxe2x80x2Rxe2x80x2)rOC(O)NR6a(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rNR6aC(O)NR6a(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rNR6aC(S)NR6a(CRxe2x80x2Rxe2x80x2)rR6d, (CRxe2x80x2Rxe2x80x2)rNR6fC(O)O(CRxe2x80x2Rxe2x80x2)rR6b, (CRxe2x80x2Rxe2x80x2)rC(xe2x95x90NR6f)NR6aR6a, (CRxe2x80x2Rxe2x80x2)rNHC(xe2x95x90NR6f)NR6fR6f, (CRxe2x80x2Rxe2x80x2)rS(O)p(CRxe2x80x2Rxe2x80x2)rR6b, (CRxe2x80x2Rxe2x80x2)rS(O)2NR6aR6a, (CRxe2x80x2Rxe2x80x2)rNR6fS(O)2NR6aR6a, (CRxe2x80x2Rxe2x80x2)rNR6fS(O)2(CRxe2x80x2Rxe2x80x2)rR6b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, and (CRxe2x80x2Rxe2x80x2)rphenyl substituted with 0-3 R6e;
alternatively, two R6 on adjacent atoms on R1 may join to form a cyclic acetal;
R6a, at each occurrence, is selected from H, methyl substituted with 0-1 R6g, C2-6 alkyl substituted with 0-2 R6e, C3-8 alkenyl substituted with 0-2 R6e, C3-8 alkynyl substituted with 0-2 R6e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R6e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R6e;
R6b, at each occurrence, is selected from H, C1-6 alkyl substituted with 0-2 R6e, C3-8 alkenyl substituted with 0-2 R6e, C3-8 alkynyl substituted with 0-2 R6e, a (CH2)rC3-6 carbocyclic residue substituted with 0-3 R6e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R6e;
R6d, at each occurrence, is selected from C3-8 alkenyl substituted with 0-2 R6e, C3-8 alkynyl substituted with 0-2 R6e, methyl, CF3, C2-6 alkyl substituted with 0-3 R6e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R6e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R6e;
R6e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR6fR6f, and (CH2)rphenyl; R6f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
R6g is independently selected from xe2x80x94C(O)R6b, xe2x80x94C(O)OR6d, xe2x80x94C(O)NR6fR6f, and (CH2)rphenyl;
R7, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CRxe2x80x2Rxe2x80x2)rNR7aR7a, (CRxe2x80x2Rxe2x80x2)rOH, (CRxe2x80x2Rxe2x80x2)rO(CRxe2x80x2Rxe2x80x2)rR7d, (CRxe2x80x2Rxe2x80x2)rSH, (CRxe2x80x2Rxe2x80x2)rC(O)H, (CRxe2x80x2Rxe2x80x2)rS(CRxe2x80x2Rxe2x80x2)rR7d, (CRxe2x80x2Rxe2x80x2)rC(O)OH, (CRxe2x80x2Rxe2x80x2)rC(O)(CRxe2x80x2Rxe2x80x2)rR7b, (CRxe2x80x2Rxe2x80x2)rC(O)NR7aR7a, (CRxe2x80x2Rxe2x80x2)rNR7fC(O)(CRxe2x80x2Rxe2x80x2)rR7b, (CRxe2x80x2Rxe2x80x2)rC(O)0(CRxe2x80x2Rxe2x80x2)rR7d, (CRxe2x80x2Rxe2x80x2)rOC(O)(CRxe2x80x2Rxe2x80x2)rR7b, (CRxe2x80x2Rxe2x80x2)rOC(O)NR7a(CRxe2x80x2Rxe2x80x2)rR7a, (CRxe2x80x2Rxe2x80x2)rNR7aC(O)NR7a(CRxe2x80x2Rxe2x80x2)rR7a, (CRxe2x80x2Rxe2x80x2)rNR7fC(O)O(CRxe2x80x2Rxe2x80x2)rR7b, (CRxe2x80x2Rxe2x80x2)rC(xe2x95x90NR7f)NR7aR7a, (CRxe2x80x2Rxe2x80x2)rNHC(xe2x95x90NR7f)NR7fR7f, (CRxe2x80x2Rxe2x80x2)rS(O)p(CRxe2x80x2Rxe2x80x2)rR7b, (CRxe2x80x2Rxe2x80x2)rS(xc2x0)2NR7aR7a, (CRxe2x80x2Rxe2x80x2)rNR7aS(O)2NR7aR7a, (CRxe2x80x2Rxe2x80x2)rNR7fS(O)2(CRxe2x80x2Rxe2x80x2)rR7b, C1-6 haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, and (CRxe2x80x2Rxe2x80x2)rphenyl substituted with 0-3 R7e;
alternatively, two R7 on adjacent atoms on R2 may join to form a cyclic acetal;
R7a, at each occurrence, is independently selected from H, methyl substituted with 0-1 R7g, C2-6 alkyl substituted with 0-2 R7e, C3-8 alkenyl substituted with 0-2 R7e, C3-8 alkynyl substituted with 0-2 R7e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R7e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7e;
R7b, at each occurrence, is selected from C1-6 alkyl substituted with 0-2 R7e, C3-8 alkenyl substituted with 0-2 R7e, C3-8 alkynyl substituted with 0-2 R7e, a (CH2)rC3-6 carbocyclic residue substituted with 0-3 R7e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7e;
R7d, at each occurrence, is selected from C3-8 alkenyl substituted with 0-2 R7e, C3-8 alkynyl substituted with 0-2 R7e, methyl, CF3, C2-6 alkyl substituted with 0-3 R7e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R7e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
R7f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
R7g is independently selected from xe2x80x94C(O)R7b, xe2x80x94C(O)OR7d, xe2x80x94C(O)NR7fR7f, and (CH2)rphenyl;
Rxe2x80x2, at each occurrence, is selected from H, C1-6 alkyl substituted with R6e, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R6e;
R8 is selected from H, C1-4 alkyl, and C3-4 cycloalkyl;
R9 is selected from, H, C1-4 alkyl, C3-4 cycloalkyl, and (CH2)xe2x80x94R1;
R10 and R10a are independently selected from H, and C1-4alkyl substituted with 0-1 R10b,
alternatively, R10 and R10a can join to form a C3-6 cycloalkyl;
R10b, at each occurrence, is independently selected from xe2x80x94OH, xe2x80x94SH, xe2x80x94NR10cR10c, xe2x80x94C(O)NR10cR10c, and xe2x80x94NHC(O)R10c;
R10c is selected from H, C1-4 alkyl and C3-6 cycloalkyl;
R11 is selected from H, C1-4 alkyl, (CHR)qOH, (CHR)qSH, (CHR)qOR11d, (CHR)qS(O)pR11d, (CHR)rC(O)R11b, (CHR)rNR11aR11a, (CHR)rC(O)NR11aR11a, (CHR)rC(O)NR11aOR11d, (CHR)qNR11aC(O)R11b, (CHR)qNR11aC(O)OR11d, (CHR)qOC(O)NR11aR11a, (CHR)rC(O)OR11d, a (CHR)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R11e, and a (CHR)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11a, at each occurrence, is independently selected from H, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, (CH2)rC3-6 cycloalkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11b, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11d, at each occurrence, is independently selected from H, methyl, xe2x80x94CF3, C2-4 alkyl, C3-6 alkenyl, C3-6 alkynyl, a C3-6 carbocyclic residue substituted with 0-3 R11e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R11e;
R11e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, xe2x80x94Oxe2x80x94C1-6 alkyl, SH, (CH2)rSC1-5 alkyl, (CH2)rNR11fR11f, and (CH2)rphenyl;
R11f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R12 is selected from H, C1-4 alkyl, (CHR)qOH, (CHR)qSH, (CHR)qOR12d, (CHR)qS(O)pR12d, (CHR)rC(O)R12b, (CHR)rNR12aR12a, (CHR)rC(O)NR12aR12a, (CHR)rC(O)NR12aOR12d, (CHR)qNR12aC(O)R12b, (CHR) NR12aC(O)OR12d, (CHR)qOC(O)NR12aR12a, (CHR)rC(O)OR12d, a (CHR)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R12e, and a (CHR)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12a, at each occurrence, is independently selected from H, C1-4 alkyl, C3-4 alkenyl, C3-4 alkynyl, (CH2)rC3-6 cycloalkyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-5 R12e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12b, at each occurrence, is independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R12e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12d, at each occurrence, is independently selected from H, methyl, xe2x80x94CF3, C2-4 alkyl, C3-6 alkenyl, C3-6 alkynyl, a C3-6 carbocyclic residue substituted with 0-3 R12e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R12e;
R12e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, xe2x80x94Oxe2x80x94C1-6 alkyl, SH, (CH2)rSC1-5 alkyl, (CH2)rNR12fR12f, and (CH2)rphenyl;
R12f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R13, at each occurrence, is independently selected from methyl, C2-4 alkyl substituted with 0-1 R13b;
R13b is selected from xe2x80x94OH, xe2x80x94SH, xe2x80x94NR13cR13c, xe2x80x94C(O)NR13cR13c, and xe2x80x94NHC(O)R13c;
R13c is selected from H, C1-4 alkyl and C3-6 cycloalkyl;
n is selected from 1 and 2;
m is selected from 0 and 1;
p, at each occurrence, is independently selected from 0, 1, and 2;
q, at each occurrence, is independently selected from 1, 2, 3, and 4;
r, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;
s, at each occurrence, is independently selected from 0 and 1; and
t, at each occurrence, is independently selected from 2, 3, and 4.
[3] In Another Embodiment, the Present Invention Provides Novel Compounds of Formula (I), Wherein
R10 and R10a are H;
m is 0;
n is 1; and
s is 0.
[4] In Another Embodiment, the Present Invention Provides Novel Compounds of Formula (I), Wherein ring B is selected from 
ring B being optionally substituted with 0-1 R5 and
R11 and R12 are H.
[5] In Another Embodiment, the Present Invention Provides Novel Compounds of Formula (I), Wherein
R5, at each occurrence, is independently selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CRR)rOH, (CRR)rSH, (CRR)rOR5d, (CRR)rSR5d, (CRR)rNR5aR5a, (CRR)rC(O)OH, (CRR)rC(O)R5b, (CRR)rC(O)NR5aR5a, (CRR)rNR5aC(O)R5b, (CRR)rNR5aC(O)OR5d, (CRR)rOC(O)NR5aR5a, (CHR)rNR5aC(O)NR5aR5a, CRR(CRR)rNR5aC(O)H, (CRR)rC(O)OR5b, (CRR)rOC(O)R5b, (CRR)rS(O)pR5b, (CRR)rS(O)2NR5aR5a, (CRR)rNR5aS(O)2R5b, and C1-6 haloalkyl;
R5a, at each occurrence, is independently selected from H, methyl, C1-6 alkyl substituted with 0-2 R5e wherein the alkyl is selected from ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl, C3 alkenyl substituted with 0-1 R5e, wherein the alkenyl is selected from allyl, C3 alkynyl substituted with 0-1 R5e wherein the alkynyl is selected from propynyl, and a (CH2)rxe2x80x94C3-4 carbocyclic residue substituted with 0-5 R5e, wherein the carbocyclic residue is selected from cyclopropyl, and cyclobutyl;
R5b, at each occurrence, is selected from C1-6 alkyl substituted with 0-2 R5e, wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl, a (CH2)rxe2x80x94C3-4 carbocyclic residue substituted with 0-2 R5e, wherein the carbocyclic residue is selected from cyclopropyl, and cyclobutyl; and
R5d, at each occurrence, is selected from methyl, CF3, C2-6 alkyl substituted with 0-2 R5e, wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, and hexyl, C3-8 alkenyl, C3-8 alkynyl, and a C3-10 carbocyclic residue substituted with 0-3 R5e.
[6] In Another Embodiment, the Present Invention Provides Novel Compounds of Formula (I), Wherein
R4 is selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, (CRR)qOH, (CRR)tSH, (CRR)tOR4d, (CRR)tSR4d, (CRR)tNR4aR4a, (CRR)qC(O)OH, (CRR)rC(O)R4b, (CRR)rC(O)NR4aR4a, (CRR)tNR4aC(O)R4b, (CRR)tOC(O)NR4aR4a, (CRR)tNR4aC(O)OR4d, (CRR)tNR4aC(O)R4b, (CRR)rC(O)OR4b, (CRR)tOC(O)R4b, (CRR)rS(O)pR4b, (CRR)rS(Q)2NR4aR4a, (CRR)rNR4aS(O)2R4b;
R, at each occurrence, is independently selected from H, methyl, ethyl, propyl, allyl, propynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R6e;
R5, at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl, (CH2)rOH, (CH2)rOR5d, (CH2)rNR5aR5a, (CH2)rC(O)OH, (CH2)rC(O)R5b, (CH2)rC(O)NR5aR5a, (CH2)rNR5aC(O)R5b, (CH2)rOC(O)NR5aR5a, (CH2)rNR5aC(O)OR5d, (CH2)rNR5aC(O)R5b, (CH2)rC (O)OR5b, (CH2)rOC(O)R5b, (CH2)rNR5aS(O)2R5b, and C1-6 haloalkyl;
R5a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl, cyclopropyl, and cyclobutyl; and r, at each occurrence, is selected from 0, 1, and 2.
[7] In Another Embodiment, the Present Invention Provides Novel Compounds of Formula (I), Wherein
R1 is selected from phenyl substituted with 0-2 R6, and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R6 wherein the heteroaryl is selected from benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.
R2 is selected from phenyl substituted with 0-2 R7, and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7 wherein the heteroaryl is selected from benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.
R4 is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl, (CRR)qOH, (CRR)sSH, (CRR)sOR4d, (CRR)sSR4d, (CRR)sNR4aR4a, (CRR)qC(O)OH, (CRR)rC(O)R4b, (CRR)rC(O)NR4aR4a, (CRR)sNR4aC(O)R4b, (CRR)sOC(O)NR4aR4a, (CRR)sNR4aC(O)OR4d, (CRR)sNR4aC(O)R4b, (CRR)rC(O)OR4b, (CRR)sOC(O)R4b, (CRR)rS(O)pR4b, (CRR)rS(O)2NR4aR4a, (CRR)rNR4aS(O)2R4b;
R4b is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and cyclopropyl;
R4d is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and cyclopropyl; and
R8 and R9 are independently selected from methyl, ethyl, propyl, i-propyl, and cyclopropyl.
[8] In Another Embodiment, the Present Invention Provides Novel Compounds of Formula (I), Wherein
R6, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CRR)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CRR)rNR6aR6a, (CRR)rOH, (CRR)rO(CRR)rR6d, (CRR)rSH, (CRR)rC(O)H, (CRR)rS(CRR)rR6d, (CRR)rC(O)OH, (CRR)rC(O)(CRR)rR6b, (CRR)rC(O)NR6aR6a, (CRR)rNR6fC(O)(CRR)rR6b, (CRR)rC(O)O(CRR)rR6d, (CRR)rNR6aC(O)NR6aR6a, (CRR)rNR6aC(S)NR6aR6a, (CRR)rOC(O)(CRR)rR6b, (CRR)rS(O)p(CRR)rR6b, (CRR)rS(O)2NR6aR6a, (CRR)rNR6fS(O)2(CRR)rR6b, (CRR)rNR6fS(O)2 NR6aR6a, C1-6 haloalkyl, and (CRR)rphenyl substituted with 0-3 R6e;
R6a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl and phenyl;
R6b, at each occurrence, is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl;
R6d, at each occurrence, is selected from methyl, CF3, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl;
R6e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR6fR6f, and (CH2)rphenyl;
R6f, at each occurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl;
R7 is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl, (CRR)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CRR)rNR7aR7a, (CRR)rOH, (CRR)rO(CH)rR7d, (CRR)rSH, (CRR)rC(O)H, (CRR)rS(CRR)rR7d, (CRR)rC(O)OH, (CRR)rC(O)(CRR)rR7b, (CRR)rC(O)NR7aR7a, (CRR)rNR7fC(O)(CRR)rR7b, (CRR)rC(O)O(CRR)rR7d, (CRR)rOC(O)(CRR)rR7b, (CRR)rNR7aC(O)NR7aR7a, (CRR)rNR7aC(O)O(CRR)rR7d, (CRR)rS(O)p(CRR)rR7b, (CRR)rS(O)2NR7aR7a, (CRR)rNR7fS(O)2(CRR)rR7b, C1-6 haloalkyl, and (CRR)rphenyl substituted with 0-3 R7e;
R7a, at each occurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, prop-2-enyl, 2-methyl-2-propenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH2cyclopropyl, and benzyl;
R7b, at each occurrence, is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, cyclopentyl, CH2-cyclopentyl, cyclohexyl, CH2-cyclohexyl, CF3, pyrrolidinyl, morpholinyl, and azetidinyl;
R7d, at each occurrence, is selected from methyl, CF3, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and cyclopropyl;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl;
R7f, at each occurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl; and
r is 0 or 1.
[9] In Another Embodiment, the Present Invention Provides Novel Compounds of Formula (I), Wherein
R7 is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F, NO2, NR7aR7a, NHC(O) NHR7a, NR7aC(O)R7b, NR7aC(O)OR7d, CF3, OCF3, C(O)R7b, NR7fC(O)NR7aR7a, NHS(O)2R7b, 
[10] In Another Embodiment, the Present Invention Provides Novel Compounds of Formula (I), Wherein
ring B is selected from 
z is xe2x80x94C(O)xe2x80x94;
R1a and R1b are selected from H and methyl, or alternatively, R1a and R1b are taken together to form xe2x95x90O;
R1 is selected from a C6-10 aryl group substituted with 0-3 R6 wherein the aryl group is selected from phenyl and naphthyl, and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N and O, substituted with 0-3 R6 wherein the heteroaryl system is selected from furyl, indolyl, and benzotriazolyl;
R2 is phenyl substituted with 0-1 R7;
R4 is selected from H, methyl, ethyl, propyl, i-propyl, butyl, I-butyl, t-butyl, pentyl, hexyl, and (CH2)rC(O)R4b;
R6 is selected from methyl, ethyl, propyl, i-propyl, butyl, F, Cl, Br, I, NO2, CN, O(CH2)rR6d, C(O)H, SR6d, NR6aR6a, OC(O)R6b, S(O)pR6b, (CHRxe2x80x2)rS(O)2NR6aR6a, CF3;
R6a is H methyl, or ethyl;
R6b is H or methyl;
R6d is methyl, phenyl, CF3, and (CH2)-phenyl;
R9 is selected from H, methyl, and (CH2)xe2x80x94R1; and
r is 0 or 1.
[11] In another Embodiment, the Present Invention Provides Novel Compounds of Formula (I), wherein the Compound is Selected from
N-[2-[[(1S,2S)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[[(2,4,6-Trimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[[(4-Benzyloxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[[(2,4-Difluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[[(2-Chloro-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[[(2-Trifluoromethyl-4-fluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[[(2,4-Dichlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[[(2-Fluoro-6-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[[(2-Chloro-5-trifluoromethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[(2,4-Dimethylbenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2S)-2-[(4-Chlorobenzyl)(methyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(4-Nitrophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(4-Isopropylphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(4-Trifluorophenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(4-Trifluoromethoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(4-Phenoxyphenyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(1-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(2-Naphthyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(3-Indolyl)methyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[1-(4-Chlorophenyl)ethyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[Bis(3-furylmethyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2R)-2-[(4-Chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2R)-2-[(4-(Methylthio)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2R)-2-[(4-(Methylsulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2R)-2-[(4-Iodobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2R)-2-[(4-(Aminosulfonyl)benzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2R)-2-[[(4-Chlorophenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2R)-2-[[(2,4-Dimethylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(1S,2R)-2-[[(4-Methylphenyl)methyl]amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Chlorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Methylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Fluorobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[Benzoylamino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Bromobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Phenoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Trifluoromethylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(5-Benzotriazolecarbonyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Iodobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Cyanobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Trifluoromethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Formylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Carbomethoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Nitrobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Aminobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Methoxybenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Methylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Methylsulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Aminosulfonylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Isopropylbenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl) benzamide;
N-[2-[[(cis)-2-[(4-Phenylthiobenzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-(N,N-diethylsulfamoyl)benzoyl)amino]cyclohexyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[(4-Trifluoromethylthiobenzoyl)amino]cyclohexyl ]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(4-Chlorophenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(3,4-Dimethylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
N-[2-[[(cis)-2-[[(4-Methylphenyl)methyl]amino]cyclopropyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide;
2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodobenzamide;
2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-chlorobenzamide;
N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-chlorobenzamide;
N-[2-[[(cis)-2-[[4-(Aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3-trifluoromethoxybenzamide;
Tert-butyl 2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;
2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethylbenzamide trifluoroacetate;
4-(Aminosulfonyl)-N-((cis)-2-{[({[2-(trifluoromethyl)anilino]carbonyl}amino)acetyl]amino}cyclohexyl)benzamide;
4-(Aminosulfonyl)-N-{(cis)-2-[({[(3-chlorophenyl)sulfonyl]amino}acetyl)amino]cyclohexyl}benzamide;
Ethyl 2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;
Methyl 2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;
Tert-butyl N-Methyl-2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;
Ethyl 2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethyl)phenylcarbamate;
2-(Benzylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-bromo benzamide;
Tert-butyl 2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(trifluoromethoxy)phenylcarbamate;
2-Amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethoxy benzamide;
2-(Allylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-(cyclopropylmethylene)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-(butyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-(propyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-(propyl)amino-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((2-methyl-2-propyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-(acetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-(Methylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethyl benzamide;
2-(Ethylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethyl benzamide;
2-(Trifluoroacetylamino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-iodomethyl benzamide;
2-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-nitro benzamide;
Iso-propyl 2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;
Tert butyl 2-[({2-[((cis)-2-{[4-(aminosulfonyl)benzoyl]amino}cyclohexyl)amino]-2-oxoethyl}amino)carbonyl]-4-(iodo)phenylcarbamate;
2-(amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-3,5-dinitro benzamide;
2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Cyclopentylmethylenecarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((cyclohexylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Isopropylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Methylsulfonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Aminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(aminosulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Allyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((2-Methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((2-methyl-2-propenyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Propyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((2-Methylpropyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylsulfonyl)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Butyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Ethylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Allylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Iso-butylaminocarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Cyclopentylaminocarbonyl)amino)-N-[2-[[(cis )-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Tert-butoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Iso-propoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Ethoxycarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Pyrrolidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Morpholinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-((Azetidinylcarbonyl)amino)-N-[2-[[(cis)-2-[[4-(methylthio)benzoyl]amino]cyclohexyl]amino]-2-oxoethyl]-5-trifluoromethyl benzamide;
2-{[1-Pyrrolidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
2-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
2-{[1-Azetidinylcarbonyl]amino}-N-{2-[((cis)-4-{[4-(methoxy)benzyl]amino}tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane;
[2-({[5-benzyloxycarbonylamino-2-(4-methylthio-benzoylamino)cyclohexylcarbamoyl]-methyl}carbamoyl)-4-trifluoromethylphenyl]carbamic acid tert-butyl ester;
{4-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)-acetylamino]-4-aminocyclohexane;
{4-(4-methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-cyclohexyl}carbamic acid benzyl ester;
1-(4-Methanesulfonylbenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)-acetylamino]cyclohexyl-4-aminocyclohexane;
1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)cyclohexane;
1-(4-Methylthiobenzoylamino)-2-[2-(2-amino-5-trifluoromethylbenzoylamino)acetylamino]-4-(3-methylureido)cyclohexane;
1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-aminocyclohexane;
1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]6-(2-propylamino)cyclohexane;
1-(4-Methylthio-benzoylamino)-2-[2-(2-Amino-5-trifluoromethyl-benzoylamino)-acetylamino]-4-aminocyclohexane;
4-(4-Methylthiobenzoylamino)-3-[2-(3-trifluoromethylbenzoylamino)acetylamino]-4-(2-propylamino)-cyclohexane;
1-(4-Methylthiobenzoylamino)-2-[2-(3-trifluoromethylbenzoylamino)acetylamino]-5-aminocyclohexane;
2-Amino-N-({2-[(4-methylthiophenylamino)methyl]cyclohexylcarbamoyl}-methyl)-5-(trifluoromethyl)benzamide;
2-Isopropylamino-N-{[(cis)2-(4-methylthiobenzylamino)-cyclohexylcarbamoyl]-methyl}-5-trifluoromethyl-benzamide;
2-(3-Isopropylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide;
2-(3-Morpholinylureido)-N-{[2-(4-methylthiobenzylamino)cyclohexylcarbamoyl]-methyl}-5-trifluoromethylbenzamide;
2-amino-N-{2-[((3S,4R)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl )benzamide;
2-Amino-N-{2-[((3R,4S)-4-{[4-(methylthio)benzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
2-amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;
N-{2-[((cis)-4-{[4-(methylthio)benzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;
2-Amino-N-{2-[((cis)-4-{[4-chlorobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
2-Amino-N-{2-[((cis)-4-{[4-ethylthiobenzyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;
N-{2-[((cis)-4-{bis[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;
2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;
2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
2-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
2-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
2-(Pyrrolidinylcarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
2-(Methylaminocarbonyl)amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
3-Amino-N-{2-[((cis)-4-{[4-methylthiobenzyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
N-{2-[((cis)-4-{[4-aminosulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;
N-{2-[((cis)-4-{[4-methylsulfonylbenzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;
2-Amino-N-{2-[((cis)-4-{[4-(methylthio)benzoyl]amino}-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-methyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;
N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-acetyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;
2-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-butyl-3-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;
2-Cyclohexylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
2-Iso-propylamino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
3-Amino-N-{2-[((cis)-4-{[4-methylthiobenzoyl]amino}-1-propyl-3-piperidinyl)amino]-2-oxoethyl}-5-(trifluoromethyl)benzamide;
1-{2-[((cis)-3-{[4-(aminosulfonyl)benzoyl]amino}-4-piperidinyl)amino]-2-oxoethyl}-3-(trifluoromethyl)benzamide;
N-{[4-Dimethylamino-2-(4-methylsulfanyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide trifluoroacetate;
N-{[2-(4-Chloro-benzylamino)-4-dimethylamino-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide trifluoroacetate;
N-{[4-Dimethylamino-2-(4-methoxy-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide trifluoroacetate; and
N-{[4-Dimethylamino-2-(4-methyl-benzylamino)-cyclohexylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide trifluoroacetate.
In another embodiment, the present invention is directed to a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention is directed to a method for modulation of chemokine or chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention is directed to a method for modulation of MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5 activity that is mediated by the CCR2 receptor comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention is directed to a method for modulation of MCP-1 activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention is directed to a method for treating or preventing disorders, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), said disorders being selected from osteoarthritis, aneurism, fever, cardiovascular effects, Crohn""s disease, congestive heart failure, autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, inflammatory bowel disease, alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
In another embodiment, the present invention is directed to a method for treating or preventing disorders, of Formula (I), wherein said disorders being selected from psoriasis, idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically- or chemically-induced brain trauma, inflammatory bowel disease, alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
In another embodiment, the present invention is directed to a method for treating or preventing disorders, of Formula (I), wherein said disorders being selected from alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis, asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
In another embodiment, the present invention is directed to a method for treating or preventing disorders, of Formula (I), wherein said disorders being selected from asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
In another embodiment, the present invention is directed to a method for treating or preventing rheumatoid arthritis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention is directed to a method for treating or preventing multiple sclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention is directed to a method for treating or preventing atherosclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention is directed to a method for treating or preventing asthma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention is directed to a method for treating or preventing inflammatory diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention is directed to a method for modulation of CCR2 activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I).
In another embodiment, ring B is selected from 
ring B being optionally substituted with 0-1 R5.
In another embodiment, ring B is selected from 
In another embodiment, Z is xe2x80x94C(O)xe2x80x94.
In another embodiment, R4 is selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, (CRR)qOH, (CHR)sSH, (CRR)tOR4d, (CHR)tSR4d, (CHR)tNR4aR4a, (CHR)qC(O)H, (CHR)rC(O)R4b, (CHR)rC(O)NR4aR4a, (CHR)tNR4aC(O)R4b, (CHR)tOC(O) NR4aR4a, (CHR)tNR4aC(O)OR4d, (CHR)tNR4aC(O)R4b, (CHR)rC(O)OR4b, (CHR)tOC(O)R4b, (CHR)rS(O)pR4b, (CHR)rS(O)2NR4aR4a, (CHR)rNR4aS(O)2R4b; and
R, at each occurrence, is independently selected from H, methyl, ethyl, propyl, allyl, propynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R6e.
In another embodiment, R4 is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl, (CRR)qOH, (CRR)tSH, (CRR)tOR4d, (CRR)tSR4d, (CRR)tNR4aR4a, (CRR)qC(O)OH, (CRR)rC(O)R4b, (CRR)rC(O)NR4aR4a, (CRR)tNR4aC(O)R4b, (CRR)tOC(O)NR4aR4a, (CRR)tNR4aC(O)OR4d, (CRR)tNR4aC(O)R4b, (CRR)rC(O)OR4b, (CRR)tOC(O)R4b, (CRR)rS(O)pR4b, (CRR)rS(O)2NR4aR4a, (CRR)rNR4aS(O)2R4b.
R4b is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and cyclopropyl; and
R4d is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and cyclopropyl.
In another embodiment, R4 is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl, (CH2)rC(O)R4b.
In another embodiment, R5, at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, allyl, propynyl, (CH2)rOH, (CH2)rOR5d, (CH2)rNR5aR5a, (CH2)rC(O)OH, (CH2)rC(O)R5b, (CH2)rC(O) NR5aR5a, (CH2)rNR5aC(O)R5b, (CH2)rOC(O)NR5aR5a, (CH2)rNR5aC(O)OR5d, (CH2)rNR5aC(O)R5b, (CH2)rC(O)OR5b, (CH2)rOC(O)R5b, (CH2)rNR5aS(O)2R5b, and C1-6 haloalkyl; and
R5a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, pentyl, hexyl, cyclopropyl, and cyclobutyl.
In another embodiment, R5, at each occurrence, is independently selected from H, (CH2)rNR5aR5a, (CH2)rNR5aC(O)R5b, and (CH2)rNR5aC(O)OR5d.
In another embodiment, R1 is selected from phenyl substituted with 0-2 R6, naphthyl substituted with 0-2 R6, and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R6 wherein the heteroaryl is selected from indolyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.
In another embodiment, R1 is selected from a C6-10 aryl group substituted with 0-3 R6 wherein the aryl group is selected from phenyl and naphthyl, and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N and O, substituted with 0-3 R6 wherein the heteroaryl system is selected from furyl, indolyl, and benzotriazolyl.
In another embodiment, R2 is selected from phenyl substituted with 0-2 R7, and a 5-10 membered heteroaryl system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7 wherein the heteroaryl is selected from benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.
In another embodiment, R2 is selected from phenyl substituted with 0-2 R7.
In another embodiment, R6, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CH2)rNR6aR6a, (CH2)rOH, (CH2)rO(CH2)rR6d, (CH2)rSH, (CH2)rC(O)H, (CH2)rS(CH2)rR6d, (CH2)rC(O)OH, (CH2)rC(O)(CH2)rR6b, (CH2)rC(O)NR6aR6a, (CH2)rNR6 C(O)(CH2)rR6b, (CH2)rC(O)O(CH2)rR6d, (CH2)rOC(O)(CH2)rR6b, (CH2)rS(O)p (CH2)rR6b, (CH2)rS(O)2NR6aR6a, (CH2)rNR6fS(O)2(CH2)rR6b, (CH2)rNR6fS(O)2 NR6aR6a, C1-6 haloalkyl, and (CH2)rphenyl substituted with 0-3 R6e;
R6a, at each occurrence, is independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl and phenyl;
R6b, at each occurrence, is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl;
R6d, at each occurrence, is selected from methyl, CF3, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl;
R6e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR6fR6f, and (CH2)rphenyl; and
R6f, at each occurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl.
In another embodiment, R6 is selected from methyl, ethyl, propyl, i-propyl, butyl, F, Cl, Br, I, NO2, CN, O(CH2)rR6d, C(O)H, SR6d, NR6aR6a, OC(O)R6b, S(O)pR6b, (CHRxe2x80x2)rS(O)2NR6aR6a, CF3;
R6a is H, methyl, or ethyl;
R6b is H or methyl; and
R6d is methyl, phenyl, CF3, and (CH2)-phenyl.
In another embodiment, R7 is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CH2)rNR7aR7a, (CH2)rOH, (CH2)rO(CH)rR7d, (CH2)rSH, (CH2)rC(O)H, (CH2)rS(CH2)rR7d, (CH2)rC(O)OH, (CH2)rC(O)(CH2)rR7b, (CH2)rC(O)NR7aR7a, (CH2)rNR7fC(O)(CH2)rR7b, (CH2)rC(O)O(CH2)rR7d, (CH2)rOC(O)(CH2)rR7b, (CH2)rNR7aC(O)NR7aR7a, (CH2)rNR7aC(O)O (CH2)rR7d, (CH2)rS(O)p(CH2)rR7b, (CH2)rS(O)2NR7aR7a, (CH2)rNR7fS(O)2(CH2)rR7b, C1-6 haloalkyl, and (CH2)rphenyl substituted with 0-3 R7e;
R7a, at each occurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and cyclopropyl;
R7b, at each occurrence, is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and cyclopropyl;
R7d, at each occurrence, is selected from methyl, CF3, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, and cyclopropyl;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, and (CH2)rphenyl; and
R7f, at each occurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, hexyl, cyclopropyl, and phenyl.
In another embodiment, R7 is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, Cl, Br, I, F, NO2, NR7aR7a, NHC(O)NHR7a, NR7aC(O)R7b, NR7aC(O)OR7d, CF3, OCF3, C(O)R7b, NR7fC(O)NHR7a, and NHS(O)2R7b.
In another embodiment, R8 is H.
In another embodiment, R9 is H, methyl, or CH2xe2x80x94R1.
In another embodiment, R11 and R12 are H.
The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., Ra) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Ra, then said group may optionally be substituted with up to two Ra groups and Ra at each occurrence is selected independently from the definition of Ra. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-8 alkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. C1-8 alkyl, is intended to include C1, C2, C3, C4, C5, C6, C7, and C8 alkyl groups. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like. xe2x80x9cC3-6 cycloalkylxe2x80x9d is intended to include saturated ring groups having the specified number of carbon atoms in the ring, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C7 cycloalkyl. C3-6 cycloalkyl, is intended to include C3, C4, C5, and C6 cycloalkyl groups
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, for example CF3, having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)).
As used herein, the term xe2x80x9c5-6-membered cyclic ketalxe2x80x9d is intended to mean 2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane and their derivatives.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. As used herein, the term aromatic heterocyclic system, or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S and is aromatic in nature.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 1H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, xcex2-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of the invention, the heterocycles include, but are not limited to, pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
Examples of heteroaryls are 1H-indazole, 2H,6H-1,5,2-dithiazinyl, indolyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, xcex2-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of the invention, examples of heteroaryls are indolyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. The present invention is intended to embody stable compounds.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention alone or in combination with other active ingredients effective to inhibit MCP-1 or effective to treat or prevent inflammatory disorders.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and work up procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A series of compounds of formulas 6 and 7 are available via the methods shown in Scheme 1. A cyclic diamine 1 can be monoprotected to provide 2. This material can be coupled to the acid 3 to yield the amide 4. Once the protecting group is removed, a reductive amination can be performed to afford target 6. This can be alkylated again to give target 7. 
A series of compounds of formulas 10 and 11 are available as shown in Scheme 2. The protecting group on intermediate 4 can be removed, and a reductive amination can be performed to yield 8. This material can be coupled to acid 9 to give target 10. A second target can be synthesized by protecting group removal from intermediate 4 and direct coupling of 9 to give the target 11. 
A series of compounds of formulas 20 and 21 are synthesized as shown in Scheme 3. A cyclic 1,2-diamine like 12 (for example, the commercially available 1,2-diaminocyclohexane) can be mono-protected as a Boc carbamate via BOC-ON (Brechbiel et al., Bioorg. Med. Chem. 1997, 5, 1925). The amine 13 can be directly coupled with 14 to yield the amide 15. In a second pathway, or a stepwise version, 13 can be coupled to 16 as the first step. The resulting amide 17 can be deprotected (N-Cbz), and then coupled to 9a to form the same 15. The N-Boc of 15 can be removed to give the key intermediate amine 19. One target can be synthesized via a reductive amination with 5 to yield 20. The second target can be synthesized by performing another reductive amination to give 21. 
A series of compounds of formulas 23 and 24 can be synthesized as shown in Scheme 4. The key intermediate 19 can be alkyated via reductive amination to give 22. The first target can be synthesized by coupling 22 with 9 to give 23. The second target can be synthesized by direct coupling of 19 with 9 to afford 24. 
A series of compounds of formulas 32 and 34 are prepared via the methods shown in Scheme 5. An amine 25 for example, the commercially available 2-benzyloxycyclopentylamine) can be protected as the carbamate 26 via Boc2O. Removal of the benzyl group affords the alcohol 27, which can be converted to the mesylate 28. The mesylate can be displaced with NaN3 to provide the azide 29. This can be reduced to the key intermediate 30. This amine can be coupled with 9 to afford the amide 31. The first target can be synthesized by deprotection with TFA followed by coupling with 3 to give 32. Another target can be synthesized from 30 by first performing a reductive amination to give 33. The amine 33 can be coupled to 9, deprotected with TFA, and coupled with 3 to afford the target 34. 
A series of compounds of formulas 39 and 40 are synthesized as shown in Scheme 6. The key intermediate 30 can be protected as the Cbz carbamate 35 via Cbz2O. The Boc group can be removed, and the acid 3 can be coupled to provide amide 37. The amide 37 can be deprotected to the amine 38, and a reductive amination can be performed to give the first target 39. The second target can be synthesized via another reductive amination on 39 to afford 40. 
As shown in Schemes 5 and 6, intermediate 30 can be converted into several target molecules. As a key intermediate, 30 can be synthesized several different ways. As shown in Scheme 7, a cyclic olefin 41 [many are available for this: 1-carbobenzyloxy-1,2,3,6-tetrahydropyridine (D""Andrea et al., J. Org. Chem. 1991, 56, 3133), 4-aminocyclohexene derivatives (Bisagni et al., J. Heterocycl. Chem. 1990, 27, 1801 or Pfister et al. Synthesis 1983, 38-40), or 3-pyrroline derivatives (Lai et al., J. Med. Chem. 1997, 40, 226)] can be oxidized to the epoxide 42 (Jacobsen et al., J. Org. Chem. 1997, 62, 4197). This can be opened with NaN3 to give the azide 43, which can be reduced. The resulting amine 44 can be protected as the N-Boc 45. This can be converted to the mesylate 46 and then the azide 47. In the final step, the azide 47 can be reduced to the key intermediate 30. 
A series of compounds of formula 58 are synthesized as shown in Scheme 8. The cyclic, unsaturated acid 48 can be converted into the 2-aminocyclocarboxylate 51 via two routes. In the first route, esterification followed by a Michael reaction (Davies et al., J. Chem. Soc. Perkin Trans. I, 1994, 1411) gives 50. Simple hydrogenation gives the 2-aminocyclocarboxylate 51. In the second route, the Michael reaction (Schneider et al., Chem Ber. 1959, 92, 1594) can be performed with ammonia to give 51 after esterification. Going forward, a Cbz group (or another appropriate protecting group) can be installed under standard conditions to afford 52. Enolization of the ester with LDA (or another appropriate base) followed by alkylation gives the substituted 53. The ester is then removed to afford the free acid 54. A Curtius (Yamada et al., Tetrahedron 1974, 30, 2151) or Hofmann reaction (Zhang et al., J. Org. Chem. 1997, 62, 6918) can then be performed to give the diamino derivative 55 (as in 35, Scheme 6). After removal of the Boc group, the right-side piece 3 can be coupled on to give the amide 57. This can be elaborated as shown in Scheme 3, 4, 5, and 6 to give the desired target 58. 
A series of compounds of formula 64 are synthesized as shown in Scheme 9. In this case, intermediate 52 (or another appropriate protecting group for Cbz) from Scheme 8 can be used as a starting point. Enolization of the ester with LDA (or another appropriate base) followed by alkylation gives the substituted 59. The ester is then removed to afford the free acid 60. A Curtius (Yamada et al., Tetrahedron 1974, 30, 2151) or Hofmann reaction (Zhang et al., J. Org. Chem. 1997, 62, 6918) can then be performed to give the diamino derivative 61 (as in 35, Scheme 6). The Cbz can be removed via hydrogenation to give the free amine 62. As before, this material can be coupled to the right-side piece 3 to give the amide 63. This can then be elaborated as shown in Scheme 3, 4, 5, and 6 to give the desired target 64. 
A series of compounds of formula 74 are synthesized as shown in Scheme 10. A cyclic ester acid 65 can be alkylated with LDA (or another appropriate base) and the electrophile R11-LG to give 66. This material can be esterified via the isourea (Mathias Synthesis 1979, 561) to afford the diester 67. Hydrolysis leads to the acid 68 which can undergo a Curtius or a Hofmann to give 69 (or another appropriate protecting group for Cbz). Once again, the ester can be alkylated with the electrophile R12-LG to provide 70. The tert-butyl ester can be removed to the acid 71, and a Curtius or Hofmann reaction provides the amine 72 (much like 35, Scheme 6). As before, 72 can be coupled to the right-side piece 3 to give the amide 73. This can then be elaborated as shown in Scheme 3, 4, 5, and 6 to give the desired target 74. 
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.